For over 130 years GTN has been used to treat angina and heart failure. However, the mechanism of GTN biotransformation has remained a mystery, and it has not been well understood why tolerance (GTN loss of clinical efficacy) develops over time.
Only recently has a mechanism for GTN biotransformation been identified. More particularly, it has been discovered that the mechanism of biotransformation of nitroglycerin is that the enzyme mitochondrial aldehyde dehydrogenase (mtALDH) catalyzes the formation of 1,2-glyceryl dinitrate and 1,2-glyceryl dinitrite therefrom, leading to production of cGMP and vascular smooth muscle relaxation and that tolerance to GTN is developed as a result of mtALDH inactivation. See Chen, Z., Zhang, J., and Stamler, J. S., Proc. Natl. Acad. Sci. USA 99 (12) 8306-8311 (published on-line Jun. 4, 2002). The above explains why those with a polymorphism in the mtALDH gene and those being treated with or ingesting or exposed to mtALDH inhibitors, are resistant to GTN therapy. The polymorphism effect is important because approximately 20% of those of Chinese descent and approximately 50% of those of Japanese descent have a polymorphism in the mtALDH gene that greatly attenuates their response to nitroglycerin. In other words, a major percentage of those of East Asian descent have not been able to benefit from actions of GTN. The mtALDH inhibitor effect is important because several common treating agents, alcoholic beverages and at least one food are mtALDH inhibitors, including acetaminophen, chloral hydrate, cyanamide, diadzin, sulfonylurea (insulin), sulfiram, ethanol and soy.
Intravenous N-acetyl cysteine (NAC), in short term studies on patients receiving continuous GTN, has been reported to reverse GTN tolerance. See Ghio, S., et al., Circulation 86: 798-802 (1992) and May, D. C., et al., N. Engl. J. Med. 317, 805-809 (1987). However, the mechanism of how this reversal may be effected has not been reported nor has NAC been recognized as a means to enable benefit from GTN therapy in those with polymorphism in the mtALDH gene or being treated with or ingesting or exposed to mtALDH inhibitors.